ABSTRACT
A homogeneous carbene-based palladium catalyst was conjugated to a cell-penetrating peptide, allowing intracellular delivery of catalytically active Pd complexes that demonstrated bioorthogonal activation of a profluorophore within prostate cancer cells.
ABSTRACT
Transition metals have been successfully applied to catalyze non-natural chemical transformations within living cells, with the highly efficient labeling of subcellular components and the activation of prodrugs. In vivo applications, however, have been scarce, with a need for the specific cellular targeting of the active transition metals. Here, we show the design and application of cancer-targeting palladium catalysts, with their specific uptake in brain cancer (glioblastoma) cells, while maintaining their catalytic activity. In these cells, for the first time, two different anticancer agents were synthesized simultaneously intracellularly, by two totally different mechanisms (in situ synthesis and decaging), enhancing the therapeutic effect of the drugs. Tumor specificity of the catalysts together with their ability to perform simultaneous multiple bioorthogonal transformations will empower the application of in vivo transition metals for drug activation strategies.
Subject(s)
Antineoplastic Agents/metabolism , Antineoplastic Agents/therapeutic use , Brain Neoplasms/drug therapy , Glioblastoma/drug therapy , Palladium/chemistry , Prodrugs/metabolism , Prodrugs/therapeutic use , Brain Neoplasms/metabolism , Catalysis , Cell Line, Tumor , Drug Delivery Systems , Fluorescent Dyes/chemistry , Glioblastoma/metabolism , Humans , Metal Nanoparticles/chemistry , Microscopy, Fluorescence , Oligopeptides/metabolismABSTRACT
As a novel prodrug activation strategy Pd(0) nanoparticles, entrapped within a modular polymeric support, were used in cell culture, to synthesise the anticancer agent PP-121 from two non-toxic precursors, thereby inducing cell death in the first example of in situ mediated drug synthesis.
Subject(s)
Antineoplastic Agents/chemical synthesis , Metal Nanoparticles/chemistry , Palladium/chemistry , Pyrazoles/chemical synthesis , Pyrimidines/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Molecular Structure , Particle Size , Pyrazoles/chemistry , Pyrazoles/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Structure-Activity Relationship , Surface Properties , Tumor Cells, CulturedABSTRACT
Bioorthogonal metal catalysed chemistry is the application of biocompatible transition metals to catalyse conventional synthetic organic chemistry reactions within a biological environment. Over the past decade, metals which were previously restricted to conventional organic synthesis have begun to be used in an increasing number of biological settings. This has been dominated by copper mediated catalysis of the azide-alkyne Huisgen cycloaddition (1,3-dipolar addition) chemistry but other, less toxic, metals such as palladium are now beginning to establish themselves in the chemical biology/chemical medicine arenas. The potential of palladium mediated chemistry in living systems now ranges from protein modifications to in cellulo synthesis or activation of drugs and suggests that palladium chemistry has the potential to become a powerful tool. In this review we highlight recent advances in Pd-mediated reactions in living systems.
Subject(s)
Biochemistry/methods , Palladium/metabolism , Catalysis , Cell Survival , HumansABSTRACT
A new approach to additions of silicon nucleophiles to imines was developed. The method is based on the phase-transfer of phenoxides by ammonium catalysts, overcoming the inability of amide adducts in promoting the reactions.
